Misfolded proteins pose a major threat to the protein homeostasis network of eukaryotic cells, particularly in terminally differentiated cells like neurons, which cannot proliferate to dilute aberrant polypeptides to a level below aggregation threshold. To safeguard the protein homeostasis network, cells have evolved several protein quality control (PQC) strategies, including chaperone-assisted protein folding, proteasomal degradation, and autophagy-mediated protein turnover. As anticipated, failures in PQC lead to accumulation of aggregationprone polypeptides, culminating in proteotoxic stress that can cause a variety of human diseases. Misfolding-associated protein secretion (MAPS) is a recently uncovered PQC mechanism, which targets misfolded cytosolic proteins to a unconventional protein secretion (UPS) pathway for export into the extracellular space. This process uses the endoplasmic reticulum (ER)-associated deubiquitinase USP19 as a receptor, which enriches misfolded proteins on the ER surface by an intrinsic chaperone activity. Subsequently, misfolded polypeptides are moved into the lumen of a population of ER-associated vesicles via an unknown protein translocation mechanism, and eventually secreted when partial or complete membrane fusion occurs between these vesicles and the plasma membrane (PM). Interestingly, many MAPS substrates are also ubiquitinated in the cell and targeted for degradation by the proteasome. The interaction of USP19 with these substrates causes the removal of ubiquitin chains by USP19, which is required for the subsequent exporting processing, at least for the substrates studied to date. Existing evidence suggests that MAPS is a supplementary PQC process, in parallel with the proteasome to alleviate proteotoxic stress caused by haploinsufficiency of the proteasome. Although USP19 is known to interact with Hsp90 and Hsp70, the chaperone requirement for MAPS has been unclear. In addition, the pathway has so far only been characterized with a few substrates, and therefore, it is unclear whether MAPS can export most or just a subset of misfolded cytosolic proteins. Moreover, among the polypeptides examined, -synuclein (-Syn), an intrinsically misfolded soluble protein implicated in Parkinsons disease is efficiently secreted, whereas the Alzheimers disease-associated Tau protein, when fused with a GFP tag was not subject to secretion by MAPS. Thus, it is unclear to what extent MAPS may contribute to the widely reported cell-to-cell transmission of misfolded proteins in neurodegenerative diseases. In addition to MAPS, several UPS routes have been reported previously. A few studies suggested exosome or extracellular vesicles as a carrier for misfolded -Syn and Tau, However, our results as well as other studies showed that misfolded -Syn and Tau released into the cell exterior are mostly not bound to vesicles. Thus, the relative contribution of different protein secretion routes to the intercellular propagation of misfolded neurotoxic proteins under physiological conditions needs to be further evaluated. Interestingly, a recent study also suggested a mechanism reminiscent of MAPS for disposal of Tau and -Syn, which involves the cytosolic chaperone HSC70, its co-chaperone DNAJC5 and a vesicle fusion regulator SNAP23. However, the functional relationship between this process and the MAPS pathway is unclear. In this study, we identify additional MAPS substrates, which now cover a collection of aberrant proteins associated with neurodegenerative diseases. Importantly, we characterize the role of two USP19-interacting chaperones; while Hsp90 is dispensable for MAPS, HSC70 and its co-chaperone DNAJC5 function together with USP19 to form a critical protein-triaging hub in MAPS. These findings unify two UPS routes that were previously deemed unrelated. Importantly, our study suggests that MAPS, as an exosome-independent secretion process, may contribute to the export of diverse neurotoxic misfolded proteins known to propagate between neurons. Because chaperone-mediated autophagy (CMA) is a known mechanism that imports cytosolic proteins bearing a specific CMA motif to lysosomes for degradation and because late endosomes and lysosomes overlap significantly in mammalian cells, we determined here whether CMA is involved in targeting protein cargoes to the lumen of late endosomes in MAPS. Using HEK293T and COS-7 cells and immunoblotting and -staining and coimmunoprecipitation methods, we show that, unlike CMA, the secretion of misfolded proteins in MAPS does not require cargo unfolding, is inhibited by serum starvation, and is not dependent on the CMA motif in cargo. Intriguingly, knockdown of lysosome-associated membrane protein 2 (LAMP2), which consists of three isoforms, including a variant proposed to form a protein channel on lysosomes for CMA, attenuated MAPS. However, this could not be attributed to the proposed channel function of the LAMP2a isoform because overexpression of a cytosolic MAPS stimulator, DnaJ heat shock protein family (Hsp40) member C5 (DNAJC5), fully rescued the secretion defect associated with LAMP2 deficiency. We conclude that, in MAPS, cargoes use a CMA-independent mechanism to enter a nondegradative prelysosomal compartment.